RESUMO
Breathing is a vital rhythmic motor behavior with a surprisingly broad influence on the brain and body. The apparent simplicity of breathing belies a complex neural control system, the breathing central pattern generator (bCPG), that exhibits diverse operational modes to regulate gas exchange and coordinate breathing with an array of behaviors. In this review, we focus on selected advances in our understanding of the bCPG. At the core of the bCPG is the preBötzinger complex (preBötC), which drives inspiratory rhythm via an unexpectedly sophisticated emergent mechanism. Synchronization dynamics underlying preBötC rhythmogenesis imbue the system with robustness and lability. These dynamics are modulated by inputs from throughout the brain and generate rhythmic, patterned activity that is widely distributed. The connectivity and an emerging literature support a link between breathing, emotion, and cognition that is becoming experimentally tractable. These advances bring great potential for elucidating function and dysfunction in breathing and other mammalian neural circuits.
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Respiração , Centro Respiratório , Animais , Encéfalo , Emoções , Mamíferos , Centro Respiratório/fisiologiaRESUMO
Inhibitory neurons embedded within mammalian neural circuits shape breathing, walking, and other rhythmic motor behaviors. At the core of the neural circuit controlling breathing is the preBötzinger Complex (preBötC), where GABAergic (GAD1/2+) and glycinergic (GlyT2+) neurons are functionally and anatomically intercalated among glutamatergic Dbx1-derived (Dbx1+) neurons that generate rhythmic inspiratory drive. The roles of these preBötC inhibitory neurons in breathing remain unclear. We first characterized the spatial distribution of molecularly defined preBötC inhibitory subpopulations in male and female neonatal double reporter mice expressing either tdTomato or EGFP in GlyT2+, GAD1+, or GAD2+ neurons. We found that the majority of preBötC inhibitory neurons expressed both GlyT2 and GAD2 while a much smaller subpopulation also expressed GAD1. To determine the functional role of these subpopulations, we used holographic photostimulation, a patterned illumination technique, in rhythmically active medullary slices from neonatal Dbx1tdTomato;GlyT2EGFP and Dbx1tdTomato;GAD1EGFP double reporter mice of either sex. Stimulation of 4 or 8 preBötC GlyT2+ neurons during endogenous rhythm prolonged the interburst interval in a phase-dependent manner and increased the latency to burst initiation when bursts were evoked by stimulation of Dbx1+ neurons. In contrast, stimulation of 4 or 8 preBötC GAD1+ neurons did not affect interburst interval or latency to burst initiation. Instead, photoactivation of GAD1+ neurons during the inspiratory burst prolonged endogenous and evoked burst duration and decreased evoked burst amplitude. We conclude that GlyT2+/GAD2+ neurons modulate breathing rhythm by delaying burst initiation while a smaller GAD1+ subpopulation shapes inspiratory patterning by altering burst duration and amplitude.
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Inalação , Animais , Camundongos , Feminino , Masculino , Inalação/fisiologia , Inibição Neural/fisiologia , Bulbo/fisiologia , Bulbo/citologia , Glutamato Descarboxilase/genética , Glutamato Descarboxilase/metabolismo , Camundongos Transgênicos , Proteínas da Membrana Plasmática de Transporte de Glicina/genética , Proteínas da Membrana Plasmática de Transporte de Glicina/metabolismo , Centro Respiratório/fisiologia , Centro Respiratório/citologia , Neurônios/fisiologia , Periodicidade , Animais Recém-NascidosRESUMO
The preBötzinger Complex (preBötC) encodes inspiratory time as rhythmic bursts of activity underlying each breath. Spike synchronization throughout a sparsely connected preBötC microcircuit initiates bursts that ultimately drive the inspiratory motor patterns. Using minimal microcircuit models to explore burst initiation dynamics, we examined the variability in probability and latency to burst following exogenous stimulation of a small subset of neurons, mimicking experiments. Among various physiologically plausible graphs of 1000 excitatory neurons constructed using experimentally determined synaptic and connectivity parameters, directed Erdos-Rényi graphs with a broad (lognormal) distribution of synaptic weights best captured the experimentally observed dynamics. preBötC synchronization leading to bursts was regulated by the efferent connectivity of spiking neurons that are optimally tuned to amplify modest preinspiratory activity through input convergence. Using graph-theoretic and machine learning-based analyses, we found that input convergence of efferent connectivity at the next-nearest neighbor order was a strong predictor of incipient synchronization. Our analyses revealed a crucial role of synaptic heterogeneity in imparting exceptionally robust yet flexible preBötC attractor dynamics. Given the pervasiveness of lognormally distributed synaptic strengths throughout the nervous system, we postulate that these mechanisms represent a ubiquitous template for temporal processing and decision-making computational motifs.SIGNIFICANCE STATEMENT Mammalian breathing is robust, virtually continuous throughout life, yet is inherently labile: to adapt to rapid metabolic shifts (e.g., fleeing a predator or chasing prey); for airway reflexes; and to enable nonventilatory behaviors (e.g., vocalization, breathholding, laughing). Canonical theoretical frameworks-based on pacemakers and intrinsic bursting-cannot account for the observed robustness and flexibility of the preBötzinger Complex rhythm. Experiments reveal that network synchronization is the key to initiate inspiratory bursts in each breathing cycle. We investigated preBötC synchronization dynamics using network models constructed with experimentally determined neuronal and synaptic parameters. We discovered that a fat-tailed (non-Gaussian) synaptic weight distribution-a manifestation of synaptic heterogeneity-augments neuronal synchronization and attractor dynamics in this vital rhythmogenic network, contributing to its extraordinary reliability and responsiveness.
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Neurônios , Centro Respiratório , Animais , Centro Respiratório/fisiologia , Reprodutibilidade dos Testes , Neurônios/fisiologia , Respiração , MamíferosRESUMO
Executing complex behaviors requires precise control of muscle activity. Our understanding of how the nervous system learns and controls motor skills relies on recording electromyographic (EMG) signals from multiple muscles that are engaged in the motor task. Despite recent advances in tools for monitoring and manipulating neural activity, methods for recording in situ spiking activity in muscle fibers have changed little in recent decades. Here, we introduce a novel experimental approach to recording high-resolution EMG signals using parylene-coated carbon nanotube fibers (CNTFs). These fibers are fabricated via a wet spinning process and twisted together to create a bipolar electrode. Single CNTFs are strong, extremely flexible, small in diameter (14-24 µm), and have low interface impedance. We present two designs to build bipolar electrode arrays that, due to the small size of CNTF, lead to high spatial resolution EMG recordings. To test the EMG arrays, we recorded the activity of small (4 mm length) vocal muscles in songbirds in an acute setting. CNTF arrays were more flexible and yielded multiunit/bulk EMG recordings with higher SNR compared with stainless steel wire electrodes. Furthermore, we were able to record single-unit recordings not previously reported in these small muscles. CNTF electrodes are therefore well-suited for high-resolution EMG recording in acute settings, and we present both opportunities and challenges for their application in long-term chronic recordings.NEW & NOTEWORTHY We introduce a novel approach to record high-resolution EMG signals in small muscles using extremely strong and flexible carbon nanotube fibers (CNTFs). We test their functionality in songbird vocal muscles. Acute EMG recordings successfully yielded multiunit recordings with high SNR. Furthermore, they successfully isolated single-unit spike trains from CNTF recordings. CNTF electrodes have great potential for chronic EMG studies of small, deep muscles that demand high electrode flexibility and strength.
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Nanotubos de Carbono , Eletromiografia/métodos , Fator Neurotrófico Ciliar , Eletrodos , Músculos/fisiologiaRESUMO
BACKGROUND: In clinical and research settings, hand dexterity is often assessed as finger individuation, or the ability to move one finger at a time. Despite its clinical importance, there is currently no standardized, sufficiently sensitive, or fully objective platform for these evaluations. METHODS: Here we developed two novel individuation scores and tested them against a previously developed score using a commercially available instrumented glove and data collected from 20 healthy adults. Participants performed individuation for each finger of each hand as well as whole hand open-close at two study visits separated by several weeks. Using the three individuation scores, intra-class correlation coefficients (ICC) and minimal detectable changes (MDC) were calculated. Individuation scores were further correlated with subjective assessments to assess validity. RESULTS: We found that each score emphasized different aspects of individuation performance while generating scores on the same scale (0 [poor] to 1 [ideal]). These scores were repeatable, but the quality of the metrics varied by both equation and finger of interest. For example, index finger intra-class correlation coefficients (ICC's) were 0.90 (< 0.0001), 0.77 (< 0.001), and 0.83 (p < 0.0001), while pinky finger ICC's were 0.96 (p < 0.0001), 0.88 (p < 0.0001), and 0.81 (p < 0.001) for each score. Similarly, MDCs also varied by both finger and equation. In particular, thumb MDCs were 0.068, 0.14, and 0.045, while index MDCs were 0.041, 0.066, and 0.078. Furthermore, objective measurements correlated with subjective assessments of finger individuation quality for all three equations (ρ = - 0.45, p < 0.0001; ρ = - 0.53, p < 0.0001; ρ = - 0.40, p < 0.0001). CONCLUSIONS: Here we provide a set of normative values for three separate finger individuation scores in healthy adults with a commercially available instrumented glove. Each score emphasizes a different aspect of finger individuation performance and may be more uniquely applicable to certain clinical scenarios. We hope for this platform to be used within and across centers wishing to share objective data in the physiological study of hand dexterity. In sum, this work represents the first healthy participant data set for this platform and may inform future translational applications into motor physiology and rehabilitation labs, orthopedic hand and neurosurgery clinics, and even operating rooms.
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Dedos , Individuação , Adulto , Humanos , Dedos/fisiologia , Extremidade Superior , Mãos/fisiologiaRESUMO
Refined grounded cognition accounts propose that abstract concepts might be grounded in brain circuits involved in mentalizing. In the present event-related potential (ERP) study, we compared the time course of neural processing in response to semantically predefined abstract mental states and verbal association concepts during a lexical decision task. In addition to scalp ERPs, source estimates of underlying volume brain activity were determined to reveal spatio-temporal clusters of greater electrical brain activity to abstract mental state vs. verbal association concepts, and vice versa. Source estimates suggested early (onset 194 ms), but short-lived enhanced activity (offset 210 ms) to verbal association concepts in left occipital regions. Increased occipital activity might reflect retrieval of visual word form or access to visual conceptual features of associated words. Increased estimated source activity to mental state concepts was obtained in visuo-motor (superior parietal, pre- and postcentral areas) and mentalizing networks (lateral and medial prefrontal areas, insula, precuneus, temporo-parietal junction) with an onset of 212 ms, which extended to later time windows. The time course data indicated two processing phases: An initial conceptual access phase, in which linguistic and modal brain circuits rapidly process features depending on their relevance, and a later conceptual elaboration phase, in which elaborative processing within feature-specific networks further refines the concept. This study confirms the proposal that abstract concepts are based on representations in distinct neural circuits depending on their semantic feature content. The present research also highlights the importance of investigating sets of abstract concepts with a defined semantic content.
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Formação de Conceito , Potenciais Evocados , Encéfalo/fisiologia , Mapeamento Encefálico , Cognição/fisiologia , Formação de Conceito/fisiologia , Potenciais Evocados/fisiologia , Humanos , Lobo Parietal , SemânticaRESUMO
Daily life often requires the coordination of our actions with those of another partner. After 50 years (1968-2018) of behavioral neurophysiology of motor control, the neural mechanisms that allow such coordination in primates are unknown. We studied this issue by recording cell activity simultaneously from dorsal premotor cortex (PMd) of two male interacting monkeys trained to coordinate their hand forces to achieve a common goal. We found a population of "joint-action cells" that discharged preferentially when monkeys cooperated in the task. This modulation was predictive in nature, because in most cells neural activity led in time the changes of the "own" and of the "other" behavior. These neurons encoded the joint-performance more accurately than "canonical action-related cells", activated by the action per se, regardless of the individual versus interactive context. A decoding of joint-action was obtained by combining the two brains' activities, using cells with directional properties distinguished from those associated to the "solo" behaviors. Action observation-related activity studied when one monkey observed the consequences of the partner's behavior, i.e., the cursor's motion on the screen, did not sharpen the accuracy of joint-action cells' representation, suggesting that it plays no major role in encoding joint-action. When monkeys performed with a non-interactive partner, such as a computer, joint-action cells' representation of the other (non-cooperative) behavior was significantly degraded. These findings provide evidence of how premotor neurons integrate the time-varying representation of the self-action with that of a co-actor, thus offering a neural substrate for successful visuomotor coordination between individuals.SIGNIFICANCE STATEMENT The neural bases of intersubject motor coordination were studied by recording cell activity simultaneously from the frontal cortex of two interacting monkeys, trained to coordinate their hand forces to achieve a common goal. We found a new class of cells, preferentially active when the monkeys cooperated, rather than when the same action was performed individually. These "joint-action neurons" offered a neural representation of joint-behaviors by far more accurate than that provided by the "canonical action-related cells", modulated by the action per se regardless of the individual/interactive context. A neural representation of joint-performance was obtained by combining the activity recorded from the two brains. Our findings offer the first evidence concerning neural mechanisms subtending interactive visuomotor coordination between co-acting agents.
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Córtex Motor/fisiologia , Neurônios/fisiologia , Desempenho Psicomotor/fisiologia , Animais , Comportamento Animal , Comportamento Cooperativo , Macaca mulatta , Masculino , Modelos Neurológicos , Atividade MotoraRESUMO
KEY POINTS: We performed a prospective electrostimulation study of the motor homunculus in 100 patients without motor deficit or brain lesion in the precentral gyrus in order to acquire accurate Montreal Neurological Institute (MNI) coordinates of the functional areas. The analysis of 248 body coordinates in the precentral gyrus showed rare inter-individual variations in the medial-to-lateral somatotopic movement organization with quite similar intensity thresholds. Electrostimulation only induced basic and stereotyped movements. We detected a relative medial-to-lateral somatotopy of the wrist/hand/global/individual fingers, with sometimes different sites for an individual muscle or movement. We found some similarities to, but also substantial differences from, the seminal work of Penfield and colleagues. We propose an updated version of the human motor homunculus and of its correlation with the somatosensory homunculus, previously defined in MNI space with a similar brain mapping technique. ABSTRACT: In this prospective electrostimulation study, based on 100 operated patients without motor deficit or brain lesion in the precentral gyrus, we acquired coordinates of the functional areas of the motor homunculus and normalized them to standard MNI space. Among 608 sites stimulated in the precentral gyrus (and 1937 in gyri nearby), 248 positive points (40%) for motor response were detected - 245 in the precentral gyrus. Positive stimulations were detected through the 'on/off' outbreak effect, and only basic movements were detected. We found no significant difference in mean intensity threshold between the motor representations of the fingers (1.94 mA), tongue and lower limbs (both 2.0 mA), or face (2.25 mA). In the precentral gyrus, the evoked body movements displayed a medial-to-lateral somatotopy in very small (often <10 mm2 ) areas. The hand region displayed multiple areas for a specific movement, with areas inducing either global or single-finger movement (with a relative medial-to-lateral somatotopy). Among these tested patients, the somatotopic organization of the intact motor cortex showed little inter-individual variations. Unlike Penfield and collaborators, we evoked no sensations such as sense of movement or desire to move, and only 2% of motor responses outside the precentral gyrus. We propose a rationalization of the standard drawing of the motor homunculus according to MNI space. We found a somatotopic correlation perpendicular to the central sulcus when matching our motor data to those previously obtained for the somatosensory homunculus.
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Terapia por Estimulação Elétrica , Córtex Motor , Mapeamento Encefálico , Mãos , Humanos , Imageamento por Ressonância Magnética , Estudos ProspectivosRESUMO
A fundamental problem in neuroscience is understanding how sequences of action potentials ("spikes") encode information about sensory signals and motor outputs. Although traditional theories assume that this information is conveyed by the total number of spikes fired within a specified time interval (spike rate), recent studies have shown that additional information is carried by the millisecond-scale timing patterns of action potentials (spike timing). However, it is unknown whether or how subtle differences in spike timing drive differences in perception or behavior, leaving it unclear whether the information in spike timing actually plays a role in brain function. By examining the activity of individual motor units (the muscle fibers innervated by a single motor neuron) and manipulating patterns of activation of these neurons, we provide both correlative and causal evidence that the nervous system uses millisecond-scale variations in the timing of spikes within multispike patterns to control a vertebrate behavior-namely, respiration in the Bengalese finch, a songbird. These findings suggest that a fundamental assumption of current theories of motor coding requires revision.
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Potenciais de Ação/fisiologia , Tentilhões/fisiologia , Contração Muscular/fisiologia , Respiração , Músculos Respiratórios/fisiologia , Animais , Curare/farmacologia , Estimulação Elétrica , Eletrodos Implantados , Eletromiografia , Feminino , Masculino , Microeletrodos , Modelos Biológicos , Fibras Musculares Esqueléticas/fisiologia , Pressão , Tempo de Reação , Músculos Respiratórios/efeitos dos fármacos , Fatores de TempoRESUMO
Mountcastle and colleagues proposed that the posterior parietal cortex contains a "command apparatus" for the operation of the hand in immediate extrapersonal space [Mountcastle et al. (1975) J Neurophysiol 38(4):871-908]. Here we provide three lines of converging evidence that a lateral region within area 5 has corticospinal neurons that are directly linked to the control of hand movements. First, electrical stimulation in a lateral region of area 5 evokes finger and wrist movements. Second, corticospinal neurons in the same region of area 5 terminate at spinal locations that contain last-order interneurons that innervate hand motoneurons. Third, this lateral region of area 5 contains many neurons that make disynaptic connections with hand motoneurons. The disynaptic input to motoneurons from this portion of area 5 is as direct and prominent as that from any of the premotor areas in the frontal lobe. Thus, our results establish that a region within area 5 contains a motor area with corticospinal neurons that could function as a command apparatus for operation of the hand.
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Dedos/fisiologia , Mãos/inervação , Neurônios Motores/fisiologia , Movimento/fisiologia , Lobo Parietal/fisiologia , Animais , Estimulação Elétrica , Feminino , Macaca mulatta , MasculinoRESUMO
Most undergraduate neuroscience courses include a neurodevelopment component. Typically, the focus is on development of the mammalian central nervous system, including the concepts of neurulation, patterning of the neural tube, and differentiation of the various cells required to build a functional nervous system. However, it can be challenging to design an affordable undergraduate laboratory exercise to reinforce these concepts for students outside of lecture. Here we describe a laboratory exercise that takes advantage of the high level of conservation in neurodevelopmental pathways using Drosophila as a model organism to illuminate the connection between cell differentiation and nervous system function. Following a lesson discussing spinal cord development, students use Drosophila larvae to assess the effects of mutations in highly conserved motor neuron differentiation genes on motor behaviors such as crawling. As outcomes of this laboratory, students are able to master important neurodevelopmental concepts, connect neurodevelopment to nervous system function, and gain experience with experimental design and data analysis.
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Central pattern generators (CPGs) are neural networks that produce rhythmic motor activity in the absence of sensory input. CPGs produce 'fictive' behaviours in vitro which parallel activity seen in intact animals. CPG networks have been identified in a wide variety of model organisms and have been shown to be critical for generating rhythmic behaviours such as swimming, walking, chewing and breathing. Work with CPG preparations has led to fundamental advances in neuroscience; however, most CPG preparations involve intensive dissections and require sophisticated electrophysiology equipment, making export to teaching laboratories problematic. Here we present an integrated approach for bringing the study of locomotor CPGs in Drosophila larvae into teaching laboratories. First, we present freely available genetic constructs that enable educators to express genetically encoded calcium indicators in cells of interest in the larval central nervous system. Next, we describe how to isolate the larval central nervous system and prepare it for live imaging. We then show how to modify standard compound microscopes to enable fluorescent imaging using 3D printed materials and inexpensive optical components. Finally, we show how to use the free image analysis programme ImageJ and freely available features in the signal analysis programme DataView to analyse rhythmic CPG activity in the larval CNS. Comparison of results to those obtained on research equipment shows that signal-to-noise levels are comparable and core features of larval CPG activity can be observed. Overall, this work shows the viability of exporting live imaging experiments to low cost environments and paves the way for new teaching laboratory exercises revolving around optical imaging of CPG activity.
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We investigated the central nervous coordination between singing motor activity and abdominal ventilatory pumping in crickets. Fictive singing, with sensory feedback removed, was elicited by eserine-microinjection into the brain, and the motor activity underlying singing and abdominal ventilation was recorded with extracellular electrodes. During singing, expiratory abdominal muscle activity is tightly phase coupled to the chirping pattern. Occasional temporary desynchronization of the two motor patterns indicate discrete central pattern generator (CPG) networks that can operate independently. Intracellular recordings revealed a sub-threshold depolarization in phase with the ventilatory cycle in a singing-CPG interneuron, and in a ventilation-CPG interneuron an excitatory input in phase with each syllable of the chirps. Inhibitory synaptic inputs coupled to the syllables of the singing motor pattern were present in another ventilatory interneuron, which is not part of the ventilation-CPG. Our recordings suggest that the two centrally generated motor patterns are coordinated by reciprocal feedforward discharges from the singing-CPG to the ventilation-CPG and vice versa. Consequently, expiratory contraction of the abdomen usually occurs in phase with the chirps and ventilation accelerates during singing due to entrainment by the faster chirp cycle.
Assuntos
Geradores de Padrão Central/fisiologia , Gryllidae/fisiologia , Atividade Motora/fisiologia , Ventilação Pulmonar/fisiologia , Vocalização Animal/fisiologia , Abdome , Animais , Sistema Nervoso Central/fisiologia , MasculinoRESUMO
Mesopontine tegmental nuclei such as the cuneiform, pedunculotegmental, oral pontine reticular, paramedian raphe and caudal linear raphe nuclei, are deep brain structures involved in arousal and motor function. Dysfunction of these nuclei is implicated in the pathogenesis of disorders of consciousness and sleep, as well as in neurodegenerative diseases. However, their localization in conventional neuroimages of living humans is difficult due to limited image sensitivity and contrast, and a stereotaxic probabilistic neuroimaging template of these nuclei in humans does not exist. We used semi-automatic segmentation of single-subject 1.1mm-isotropic 7T diffusion-fractional-anisotropy and T2-weighted images in healthy adults to generate an in vivo probabilistic neuroimaging structural template of these nuclei in standard stereotaxic (Montreal Neurological Institute, MNI) space. The template was validated through independent manual delineation, as well as leave-one-out validation and evaluation of nuclei volumes. This template can enable localization of five mesopontine tegmental nuclei in conventional images (e.g. 1.5T, 3T) in future studies of arousal and motor physiology (e.g. sleep, anesthesia, locomotion) and pathology (e.g. disorders of consciousness, sleep disorders, Parkinson's disease). The 7T magnetic resonance imaging procedure for single-subject delineation of these nuclei may also prove useful for future 7T studies of arousal and motor mechanisms.
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Processamento de Imagem Assistida por Computador/métodos , Imageamento por Ressonância Magnética/métodos , Neuroimagem/métodos , Tegmento Mesencefálico/diagnóstico por imagem , Adulto , Imagem de Tensor de Difusão/métodos , Imagem Ecoplanar/métodos , Feminino , Humanos , MasculinoRESUMO
With the advent of rodent models of L-DOPA-induced dyskinesia (LID), a growing literature has linked molecular changes in the striatum to the development and expression of abnormal involuntary movements. Changes in information processing at the striatal level are assumed to impact on the activity of downstream basal ganglia nuclei, which in turn influence brain-wide networks, but very little is actually known about systems-level mechanisms of dyskinesia. As an aid to approach this topic, we here review the anatomical and physiological organisation of cortico-basal ganglia-thalamocortical circuits, and the changes affecting these circuits in animal models of parkinsonism and LID. We then review recent findings indicating that an abnormal cerebellar compensation plays a causal role in LID, and that structures outside of the classical motor circuits are implicated too. In summarizing the available data, we also propose hypotheses and identify important knowledge gaps worthy of further investigation. In addition to informing novel therapeutic approaches, the study of LID can provide new clues about the interplay between different brain circuits in the control of movement.
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Antiparkinsonianos/toxicidade , Encéfalo/fisiopatologia , Discinesia Induzida por Medicamentos/fisiopatologia , Levodopa/toxicidade , Vias Neurais/fisiopatologia , AnimaisRESUMO
Respiratory complications in patients with spinal cord injury (SCI) are common and have a negative impact on the quality of patients' lives. Systemic administration of drugs that improve respiratory function often cause deleterious side effects. The present study examines the applicability of a novel nanotechnology-based drug delivery system, which induces recovery of diaphragm function after SCI in the adult rat model. We developed a protein-coupled nanoconjugate to selectively deliver by transsynaptic transport small therapeutic amounts of an A1 adenosine receptor antagonist to the respiratory centers. A single administration of the nanoconjugate restored 75% of the respiratory drive at 0.1% of the systemic therapeutic drug dose. The reduction of the systemic dose may obviate the side effects. The recovery lasted for 4 weeks (the longest period studied). These findings have translational implications for patients with respiratory dysfunction after SCI. SIGNIFICANCE STATEMENT: The leading causes of death in humans following SCI are respiratory complications secondary to paralysis of respiratory muscles. Systemic administration of methylxantines improves respiratory function but also leads to the development of deleterious side effects due to actions of the drug on nonrespiratory sites. The importance of the present study lies in the novel drug delivery approach that uses nanotechnology to selectively deliver recovery-inducing drugs to the respiratory centers exclusively. This strategy allows for a reduction in the therapeutic drug dose, which may reduce harmful side effects and markedly improve the quality of life for SCI patients.
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Diafragma/fisiopatologia , Receptor A1 de Adenosina/metabolismo , Paralisia Respiratória/tratamento farmacológico , Paralisia Respiratória/fisiopatologia , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/fisiopatologia , Xantinas/administração & dosagem , Antagonistas do Receptor A1 de Adenosina/administração & dosagem , Antagonistas do Receptor A1 de Adenosina/química , Animais , Diafragma/efeitos dos fármacos , Masculino , Força Muscular/efeitos dos fármacos , Nanoconjugados/administração & dosagem , Nanoconjugados/química , Ratos , Ratos Sprague-Dawley , Recuperação de Função Fisiológica/efeitos dos fármacos , Mecânica Respiratória/efeitos dos fármacos , Paralisia Respiratória/etiologia , Traumatismos da Medula Espinal/complicações , Resultado do Tratamento , Conjugado Aglutinina do Germe de Trigo-Peroxidase do Rábano Silvestre/química , Conjugado Aglutinina do Germe de Trigo-Peroxidase do Rábano Silvestre/farmacocinética , Xantinas/químicaRESUMO
In 2014, the case of a 24-year-old woman who had just discovered she was born without a cerebellum made headlines around the world. The details of this case were combined with other published cases of cerebellar agenesis to create an active learning exercise for an undergraduate developmental and systems neuroscience course. By reading an intriguing narrative and answering questions in stages, students work together to apply and extend their knowledge of brain development and cerebellar function. The case can be used to introduce new information in a "flipped classroom" setting or as an interactive exam review.
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Many motor control systems generate multiple movements using a common set of muscles. How are premotor circuits able to flexibly generate diverse movement patterns? Here, we characterize the neuronal circuits that drive the distinct courtship songs of Drosophila melanogaster. Male flies vibrate their wings toward females to produce two different song modes-pulse and sine song-which signal species identity and male quality. Using cell-type-specific genetic reagents and the connectome, we provide a cellular and synaptic map of the circuits in the male ventral nerve cord that generate these songs and examine how activating or inhibiting each cell type within these circuits affects the song. Our data reveal that the song circuit is organized into two nested feedforward pathways with extensive reciprocal and feedback connections. The larger network produces pulse song, the more complex and ancestral song form. A subset of this network produces sine song, the simpler and more recent form. Such nested organization may be a common feature of motor control circuits in which evolution has layered increasing flexibility onto a basic movement pattern.